The long-term objective of this research proposal is to develop a means to reconstruct the neural circuit that degenerates in Parkinson's disease (PD) - that is, the nigrostriatal pathway. While current therapy (levadopa treatment) for PD may alleviate symptoms for a while, there is still no way to halt or reverse the neurodegeneration. Since 1% of the population over the age of 65 is affected by PD, and the prevalence increases with increasing age, research into better therapies and an eventual cure for PD is important for our aging population. Cellular replacement is not a new idea in PD research, but this proposal differs from most previous efforts by attempting an anatomically and physiologically correct reestablishment of the nigrostriatal pathway, effecting a more complete behavioral recovery. Molecular cues to guide growth of dopaminergic neurons will be identified in vitro, and adenoviral vectors will be used to express these molecules between the substantia nigra (SN) and the striatum in hemiparkinsonian rats. When dopaminergic neurons are subsequently transplanted into the SN, their axons should grow along the growth-supportive pathway, ending in the striatal target. Success will be evaluated with detailed histological and behavioral analyses.